We have been developing strategies to utilize nitric oxide (NO) in cancer treatment. In addition to the use of synthetic NO donors, we are researching the mechanisms that control the endogenous cellular production. We have recently discovered that inhibition of Nitric oxide synthase (NOS) given after chemotherapy or radiation treatment enhances tumor re-growth delay. Given that there are a number of clinically available NOS inhibitors this could have potential clinical applications. We have recently characterized the NO levels that are required to activate and stabilize key proteins involved in carcinogenesis, p53, ERK and HIF. We have extended this work to show that levels of NO are critical to angiogenesis and that NO and TSP-1 regulate each other pathways. Our extension of the understanding of angiogenic responses and nitric oxide has lead us to understand the regulation of Matrix Metalloproteases (MMP) by NO . Our findings suggest that under inflammatory response MMP are regulated by two different mechanisms, biologocal signlaing and direct chemical modification. The first is via TIMP through cGMP. The second are through chemical reactivity of RNS. We demonstrated that MMP9 secreted from macrophage was a critical facotr in the NO mediated wound healing response. Another important area of reseach is our investigation of nitroxyl (HNO) which has been shown to have some unique properties from its redox cousin nitric oxide. Though NO was discovered in the 1980s and many of the higher oxides of nitrogen have been studied, the reduced nitrogen oxide such as HNO have just recently begun to be examined. This small molecule has been shown to have promising effects in the preconditioning against myocardiac infarction and improve contractility under heart failure conditions. We have also found that HNO can regulate the activity of P450, COX-2 and TGFbeta implicating a possible role in cancer. One of the major questions concerning its biology is whether HNO is an intermediate generated in vivo. We have developed methods to determine if HNO can be generated from different biochemical mechanism involving proteins and other molecules can interact with other biological targets. One of the largest discovery in this project is that HNO donors may be an effective treatment for heart failure as well as preconditioning the coronary against ischemia reperfusion injury or heart attacks. This projects future goal is to determine mechanism of endogenous generation of HNO as well as find different pharmacological properties that may be useful in cancer treatment as well as heart disease. .